IL-21 dependent immunity to microsporidia

对微孢子虫的 IL-21 依赖性免疫

• 批准号: 8698505
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 38.9万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698505
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Animals; Automobile Driving; Bacteria; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Data; Development; Disease Progression; Effector Cell; Elderly; Ensure; Exhibits; Functional disorder; Generations; Goals; HIV; HIV Infections; Hand; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immunity; Immunocompromised Host; Individual; Infection; Infection Control; Infectious Agent; Interleukin-2; Kinetics; Laboratories; Life; Light; Link; Maintenance; Measurable; Memory; Microsporidia; Microsporidiosis; Modeling; Morbidity - disease rate; Nature; Opportunistic Infections; Parasites; Patients; Play; Population; Production; Publishing; Regimen; Reporting; Risk; Role; Signal Transduction; Source; System; T cell response; T-Lymphocyte; TNF gene; Testing; Vaccinated; Vaccines; Virus; Virus Diseases; base; cytokine; exhibitions; long term memory; mortality; oral pathogen; pathogen; response; success

DESCRIPTION (provided by applicant): Due to their ability to produce cytokines and exhibit cytolytic activity against infected targets, CD8+ T cells are critical role for protection against number of intracellular pathogens. Since last few years it has been reported that superior control of replication of these infectious agents is dependent on the ability of these cells to display multiple functions. Many of these studies have been carried out with HIV infected individuals and it has been demonstrated that non-progressors (those who do not develop symptomatic infection) maintain high levels of multifunctional response, which is not the case in the subjects where infection progresses. Moreover, the success of vaccine regimens against viral infection has also been linked to its ability to induce robust multifunctional CD8+ T cell response. Recent data from our laboratory suggests that importance of multifunctional cells cannot be restricted to viral infections and can be extended to fungal pathogens like microsporidia an important opportunistic pathogen that causes morbidity/ mortality in HIV infected population. Preliminary data for the proposal demonstrates that host protection is strongly dependent on its ability to develop a strong polyfunctional CD8+ T cell response. However, factor (s) responsible for the development of robust polyfunctional SLEC (short-lived effector cell) and MPEC (memory precursor effector cell) response has not been well studied and cytokine responsible for their induction has not been identified. Preliminary studies from our laboratory suggest that FTH (Follicular T helper cells) subset of CD4+ T cells, main producers of IL- 21 play a pivotal role in the induction of thi response to microsporidial infection. In this proposal we plan to study the induction of FTH immunity against the microsporidial infection and their importance and mechanism in the development of multifunctional SLEC/ MPEC response. Moreover, in an immune-compromised situation like HIV infection, when CD4+ T cell responses are severely down-regulated alternate mechanism(s) that can be explored to induce and maintain the multifunctional ability of these cells will be tested. The proposal comprises of three specific aims. In the first specific aim kinetics, induction and mechanism of induction of FTH response against microsporidial infection will be determined. Further their role in the development of multifunctional SLEC and MPEC response will be assayed. The second specific aim will involve the role of FTH/IL-21 in the transition of multifunctional SLEC and MPEC population to memory response. Further, importance of FTH/IL-21 in maintenance of long-term memory response will be assayed. Finally in the third specific aim role of gd T cells in the development of functional SLEC and MPEC response in the absence of optimal CD4+ T cell immunity, like during HIV infection will be determined.

描述（由申请人提供）： 由于 CD8+ T 细胞能够产生细胞因子并对感染目标表现出细胞溶解活性，因此它们在抵御多种细胞内病原体方面发挥着关键作用。自上次以来 几年来，据报道，对这些传染原复制的卓越控制取决于这些细胞表现出多种功能的能力。其中许多研究都是针对艾滋病毒感染者进行的，并且已经证明，非进展者（那些没有出现症状感染的人）保持高水平的多功能反应，而感染进展的受试者则并非如此。此外，针对病毒感染的疫苗方案的成功也与其诱导强大的多功能 CD8+ T 细胞反应的能力有关。我们实验室的最新数据表明，多功能细胞的重要性不仅限于病毒感染，还可以扩展到真菌病原体，如微孢子虫，这是一种重要的机会性病原体，可导致艾滋病毒感染人群发病/死亡。该提案的初步数据表明，宿主保护在很大程度上取决于其产生强大的多功能 CD8+ T 细胞反应的能力。然而，尚未充分研究负责产生强大的多功能 SLEC（短命效应细胞）和 MPEC（记忆前体效应细胞）反应的因子，并且尚未确定负责诱导它们的细胞因子。我们实验室的初步研究表明，FTH（滤泡 T 辅助细胞）是 CD4+ T 细胞的子集，是 IL-21 的主要产生者，在诱导对微孢子虫感染的反应中发挥着关键作用。在本提案中，我们计划研究针对微孢子虫感染的 FTH 免疫诱导及其在多功能 SLEC/MPEC 反应发展中的重要性和机制。此外，在 HIV 感染等免疫受损的情况下，当 CD4+ T 细胞反应严重下调时，将测试可探索诱导和维持这些细胞多功能能力的替代机制。该提案包括三个具体目标。在第一个具体目标中，将确定针对微孢子虫感染的 FTH 反应的诱导和诱导机制。进一步分析它们在多功能 SLEC 和 MPEC 反应发展中的作用。第二个具体目标将涉及 FTH/IL-21 在多功能 SLEC 和 MPEC 群体向记忆反应转变中的作用。此外，还将分析 FTH/IL-21 在维持长期记忆反应中的重要性。最后，在第三个具体目标中，在缺乏最佳 CD4+ T 细胞免疫的情况下（例如在 HIV 感染期间），将确定 gd T 细胞在功能性 SLEC 和 MPEC 反应发展中的作用。